A New Tune for a Different Kind of ACCORDION

ORAL DOSING IS BY FAR THE MOST CONVENIENT ROUTE for drug administration when systemic absorption is required. However, for many drugs, the blood levels that can be achieved by the oral route are often limited by rapid drug elimination and significant absorption only occurring in a short section of the GI tract. Therapeutic blood levels are achieved for only a short period of time, as the dosage form releasing the drug transits out of the stomach and along the GI tract. This requires frequent dosing, but the potential for poor patient compliance means an inadequate amount of the active ingredient is absorbed or actually reaching the systemic circulation, resulting in fluctuating levels and varying toxicity associated with unavoidably high Cmax levels. All these factors make the safety and efficacy profile of the drug sub-optimal and difficult to control, and are an outcome of the inherent pharmacokinetic properties of the drug. Standard extended release formulations do not offer much advantage as, once they leave stomach, the released drug is no longer in a region where it can be absorbed. In some cases, these challenges are so significant that a drug cannot be dosed orally, leaving either parenteral routes as the only alternative or switching to another drug altogether. For a drug in development this can mean the termination of the development program.

The phenomonen of an absorption window is closely related to the chemical and physical properties of the drug molecule, the luminal milieu and the mechanisms of its transport across the intestinal barrier to the blood circulation. Active substances that are selectively transported by carriers that are prevalent in the upper parts of the GI include, amino acid analogues (widely used as CNS drugs), nucleoside analogues (used as anti-viral drugs), peptidomimetic molecules (used in cardiovascular treatment) and beta-lactam antibiotics.

A rational approach to enhance bioavailability and improve the pharmacokinetic/ pharmacodynamic profile is to retain the drug reservoir proximal to its absorption area, i.e. in the stomach and to release the drug as a controlled oral infusion for a prolonged period of time.

The need for gastroretentive dosage forms (GRDFs) to make the most use of drugs with unforgiving characteristics has led to extensive efforts in both academia and industry in the development of such drug delivery systems.

MARKET VALUE OF ORAL GASTRIC RETENTION DRUGS

The market value of drugs that would benefit from gastric retention is large, estimated at more than $30 billion. The categories of drugs that may be significantly improved include:

• Amino Acids Analogs (e.g., various drugs for CNS disorders)

• Small Peptide Peptidomimetics (e.g., cardiovascular drugs)

• Beta-lactams and Cephalosporins (antibiotics)

• Nucleoside Analogs (e.g., various anti viral drugs)

Another scenario that could benefit from gastric retention and controlled release in the stomach would be the directed local therapy in the treatment of pathologies located in the stomach, the duodenum or upper small intestine.

Reformulation in a controlled release - gastric retention (CRGR) system offers a unique approach to life cycle management (LCM) of drugs where the patent is expiring, or generic forms have already appeared. LCM allows faster and less risky development programs, with three times higher success rate at Phase I compared to new drug entities, and as such are widely utilized by pharmaceutical companies to maximize revenues.

At the other extreme, a revolutionary business opportunity for an effective novel and efficient gastric retention CR system might be to convert the route of administration for certain drugs i.e., from injectable to oral.

THE FAST AND FED STATES OF THE STOMACH

The process of GI transit in humans and its implications on attaining gastric retention and drug delivery are well appreciated. Gastric emptying is controlled by the feeding status: high calorie and high fat food extend the time before emptying of the stomach of solids and emptying time is typically three to five hours. In the fasted state, the stomach is evacuated of its remaining content by the "house keeping" wave that occurs irregularly. Most objects larger than 20 mm will be retained in a fed stomach, while objects smaller than 5 mm are likely to be evacuated even in the presence of a meal. To achieve prolonged gastric retention, a drug must be delivered in a formulation that resists evacuation by propagated waves of contraction in the stomach, and can also withstand the harsh environment of the stomach, which is functionally designed to triturate solid material.

DEVELOPMENT OF THE ACCORDION PILL GASTRIC RETENTION SYSTEM

Fig. 1: The GRDF laminated structure (left), which is folded in a standard capsule like an accordion (middle), and is unfolded in the stomach (right) as visualized by gastroscopy of a healthy volunteer 15 minutes after swallowing.

Considering the environment of the stomach, a gastric retention (GR) system should provide effective retention in the stomach to extend exposure while maintaining the convenient and familiar appearance of conventional oral formulations to facilitate patient compliance. It is important that patients are not obliged to always take the GR-formulated drug with a high calorie meals, but can carry on with their regular diet. The oral form should provide sufficient drug loading capacity; should degrade and be evacuated once the drug release phase is over; should display no effect on gastric motility including emptying pattern of subsequently ingested doses, and be free from adverse local effects. In addition, to achieve optimal release profiles for drugs with varying characteristics, fine control of the release rate should also be possible. Ideally, control over drug release rate and release profiles should be independent of the retention properties of the system. The accordion-like gastric retentive dosage form (GRDF) was designed and developed to meet these demands (Figure 1). The GRDF consists of a laminate of polymeric layers, some of which are responsible for the mechanical properties required to achieve retention in the stomach, while others are responsible for holding the drug and controlling its release rate. The laminate is folded and enclosed inside a standard gelatin capsule. Once exposed to the gastric fluid, the capsule dissolves, the GRDF unfolds and starts to release the drug.

Fig. 2: MRI images of magnetite-labeled GRDF in a human volunteer, given after a light breakfast. At five hours post dosing, a lunch of about 800 kcal was given. At 24 hours, the labeled GRDF was not visualized anywhere in the GI tract, implying evacuation of the dosage form within 24 hours.

The GRDF has been studied in a series of clinical trials to assess its retention in the stomach, as well as its safety and efficacy of enhancing the absorbance of a model drug for drugs that are poorly absorbed due to a transporter-dependent, region-specific absorbance pattern. Highlights of recent clinical trials are described below.

STUDY OF RETENTION PROPERTIES

To follow the fate of a dosage form that is designed to be retained in the stomach, the accordion-like dosage form was formulated with ferric oxide, a MRI contrasting agent, in the drug reservoir film. Human volunteers were given the magnetite-labeled GRDFs after eating a light breakfast (282 kcal). The retained dosage forms could be visualized with MRI and typical results are presented in Figure 2. The GRDF was shown to move in the stomach during the retention phase, and did not appear to obstruct the pylorus, thus minimizing the risk of interference with the passage of gastric contents into the duodenum.

Fig. 3: y-scintigraphy images of (from left to right): labeled meal immediately after dosing; the GRDF immediately after dosing; 50 percent evacuation of the meal (0.77+0.12 h vs. 0.21+0.13 h (SE) for the control tablet); (D) the GRDF retained in the stomach after the meal has fully evacuated 14.3+3.7 h vs. 3.7+0.4 h for (SE) the control tablet.

In this clinical trial all five subjects retained the dosage form for six hours, four out of the five retained it for 12 hours. In all five subjects, the GRDF was evacuated from the stomach by 24 hours (MRI images were not taken between 12 and 24 hours). This study was repeated with a group of eight volunteers, where six of eight subjects retained the GRDF for 10.5 hours, all evacuated the GRDF by 24 hours (no images were taken between 10.5 and 24 hours). One person evacuated between three and 4.5 hours; the other person evacuated between 4.5 and six hours.

FOOD EMPTYING IN THE PRESENCE OF THE GRDF

An important safety concern with any expandable (or swelling) gastric retentive dosage form is the possible hindrance of emptying of food or of other drugs. To evaluate this, the GRDF was labeled with a ¹¹¹In - marker and taken with ⁹⁹mTc - labeled food. The food and the GRDF could therefore be followed simultaneously by a Y-camera. A large non-disintegrating tablet, also labeled with ¹¹¹In was used as a comparator arm with the labeled food in this study. The trial was carried out in a random cross-over design in eight healthy volunteers. Figure 3 presents typical images obtained, showing the meal in the ⁹⁹mTc channel and the GRDF in the ¹¹¹In channel.

In this trial, the mean T50 and T90 for food evacuation from the stomach were 0.77(+0.12) hour and 1.43(+0.13) hour for the GRDF, while the control times were 0.71(+0.13) hour and 1.51(+0.21) hour, respectively. We therefore conclude that the GRDF does not affect food emptying. This Y-scintigraphy trial also confirmed the retention times observed by MRI, since in four volunteers the GRDF evacuated from the stomach between 18 and 24 hours (no images were taken between these two times), two evacuated by 5.5 hours, one by four hours and one by 3.75 hours.

INCREASED BIOAVAILABILITY

The same GRDF platform was used for a riboflavin formulation (RF), which was selected as a model drug substance. This vitamin is known to be preferentially absorbed in the upper GI by a specific, saturable transporter. The cumulative release rate of riboflavin in KCl/HCl buffer at pH 2.2 was 80 percent at 10 hours, in the same range of time that the GRDF was shown to be retained in the stomach (Figure 4).

In a double-cross-over trial, the RF-GRDF was dosed after a light breakfast to seven volunteers, affording a 65 percent increase in bioavailability of the API as compared to an immediate release formulation. The absorption phase was extended from ~4 hours in the control capsule to ~8 hours with the GRDF, Cmax was similar in both cases (78 ng/ml) while T_apical was extended from ~1.5 hours to ~5 hours (corresponding T_maxvalues were 1.5 and 3.5 hours respectively). The mean plasma concentration of RF of the GRDF and the control IR formulation are both presented in Figure 5. This clinical trial confirmed that holding of the drug reservoir in the stomach while releasing the drug continuously over the same period of time can effectively enhance bioavailability, even when the absorption is limited by saturation of a specific transporter.

Fig. 4: In vitro release profile of RF5P in KCl/HCl buffer, pH 2.2.

CONCLUSIONS

Recent clinical studies have demonstrated that Intec's Accordion Pill achieves outstanding gastric retention with controlled drug release. This unique approach offers a remarkable opportunity whereby reformulation can significantly enhance the safety, efficacy and convenience of many orally administered drugs. -PFQ

Fig. 5: Mean plasma concentration of RF dosed after a light meal with an IR formulation (blue) or a GRDF (pink).

References:

A.A. Deshpande, C.T. Rhodes, N.H. Shah, A.W. Malick, Controlled-release drug delivery systems for prolonged gastric residence: an overview, Drug Dev. Ind. Pharm. 22 (6) (1996) 531-539.

S. S. Davis, Formulaiton strategies for absorption windows, Drug Discovery Today, 10 (2005) 249-256.

N. Washington, C. Washington, C.G. Wilson, Physiological Pharmaceutics. II, Taylor and Francis, New York, 2001.

A. Hoffmann, D. Stepensky, E. Lavy, S Eyal, E. Klausner, M. Friedman, Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms, Int. J. of Pharm. 277 (2004) 141-153.

L. Kagan, N. Lapidot, M. Afargan, D. Kirmayer, E. Moor, Y. Mardor, M. Friedman, A. Hoffman, Gastroretentive Accordion Pill: Enhancement of riboflavin bioavailability in humans, J. Control. Release 113 (2006) 208-215.